Optically active alcohols are useful as an asymmetric source for synthesizing various optically active compounds. Typically, optically active alcohols are produced through optical resolution of racemates or asymmetric synthesis. In particular, the technology for optically active alcohol production through asymmetric synthesis is recognized to be essential to produce optically active alcohols on a large scale.
(R)-3-quinuclidinol is an industrially useful optically active alcohol. Optically active (R)-3-quinuclidinol has been used as an important intermediate to produce a variety of physiologically active or pharmacological active agents, for example, in therapeutic agents for arteriosclerosis, which have the activity of inhibiting squalene synthase, bronchodilators having antagonistic action to the muscarinic receptor, agents suppressing gastrointestinal motility, etc. (Unexamined Published Japanese Patent Application No. (JP-A) Hei 8-134067; EP-404737A2; EP-424021A1; WO92/04346; and WO93/06098).
So far known methods for producing optically active 3-quinuclidinol include, a method where the compound is produced through optical resolution of the acetylated form of 3-quinuclidinol racemate with tartaric acid, followed by hydrolysis (Acta Pharm. Suec. 16(4), 281-3 (1979)).
Another known production method using a microorganism or enzyme comprises selective asymmetric hydrolysis of (S)-3-quinuclidinol ester by allowing one of the microorganisms or enzymes described below to react to the racemate of 3-quinuclidinol ester that is a raw material, and the subsequent hydrolysis of residual (R)-3-quinuclidinol ester.
Subtilisin protease (U.S. Pat. No. 5,215,918);
Esterases derived from the genus Aspergillus or the genus Pseudomonas (JP-A Hei 10-210997); and
Cells of microorganisms belonging to the genus Aspergillus, the genus Rhizopus, the genus Candida, and the genus Pseudomonas (JP-A Hei 10-136995), and enzymes derived therefrom.
In addition, an alternative production method has been reported, which comprises selective asymmetric hydrolysis of (R)-3-quinuclidinol ester by contacting horse serum esterase with the racemate of 3-quinuclidinol ester that is a raw material (Life Sci. 21(9), 1593-302 (1977)). Further, there is another known method where, using the racemate of 3-quinuclidinol as a raw material, the R form is obtained by converting, with subtilisin protease, only the S form to (S)-3-quinuclidinyl butyrate (German Patent No. 19715465).
However, the product obtained by these production methods has only low optical purity. In addition, these production methods have complicated synthesis steps. Thus, any of the methods described above cannot be said as the methods for simply and economically producing (R)-3-quinuclidinol.
Additional known methods for producing optically active 3-quinuclidinol from 3-quinuclidinone, comprises asymmetric reduction using microorganisms or enzymes (JP-A Hei 10-243795; JP-A Hei 11-196890; JP-A 2000-245495; Abstract (2001) The Japan Agricultural Chemical Society, pp. 371 3Y7a9). In this reaction, the optically active compound is produced directly by incubating a substrate compound with a wild-type microorganism. The reaction consists of a single reaction step, thus the method has greatly been simplified. However, there still remain some problems; the optical purity of the product is low and the concentration of the product obtained is also low.